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How to prevent and treat pharmacological hypoglycemias
Como prevenir y tratar las hipoglucemias farmacológicas
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El uso de fármacos marcados con «*» se indica de forma jerárquica, en función de sus beneficios y/o perfil favorable de efectos adversos; el resto de fármacos incluidos en cada epígrafe deben usarse con precaución por este mismo motivo.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. Reyes García, P. Mezquita Raya" "autores" => array:2 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "Reyes García" ] 1 => array:2 [ "nombre" => "P." 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Reyes García, P. Mezquita Raya" "autores" => array:2 [ 0 => array:3 [ "nombre" => "R." "apellidos" => "Reyes García" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 1 => array:4 [ "nombre" => "P." "apellidos" => "Mezquita Raya" "email" => array:1 [ 0 => "pmr.csp@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Unidad de Endocrinología, Hospital General Universitario Rafael Méndez, Lorca, Murcia, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Endocrinología, Nutrición y Riesgo Vascular, Complejo Hospitalario Torrecárdenas, Almería, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Endocrinología, Clínica San Pedro, Almería, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Como prevenir y tratar las hipoglucemias farmacológicas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "<span class="elsevierStyleItalic">Source</span>: Adapted from the AACE Comprehensive Diabetes Management Algorithm.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> The algorithm states the treatment recommendations of the AACE based on the initial HbA<span class="elsevierStyleInf">1c</span> values and the presence or absence of symptoms. The use of drugs marked with * is indicated hierarchically, based on its benefits and/or favorable profile of adverse effects; the rest of the drugs included in each heading should be used with caution for this reason." "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1691 "Ancho" => 1589 "Tamanyo" => 242642 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Treatment algorithm for type 2 diabetes of the American Association of Clinical Endocrinologists.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">The clinical problem</span><p id="par0005" class="elsevierStylePara elsevierViewall">Proper glycemic control is one of the fundamental pillars in the treatment of diabetes due to its recognized effect on the prevention of chronic microvascular complications.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Achieving this objective in the early phases of diabetes is a priority; the current recommendations therefore advise individualizing the objective of glycemic control based on the patient's characteristics and the evolution of the diabetes.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However, there is an inverse relationship between treatment intensification and the risk of hypoglycemia, especially in cases of treatment with sulfonylureas, glinides and insulin.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Therefore, for young patients with no cardiovascular disease and a short evolution of the diabetes, achieving strict glycemic control is recommended. This control is defined as an HbA1c level less than 6.5%, provided this is achieved without increasing the risk of hypoglycemia. In contrast, for older patients, those with cardiovascular disease, those with advanced microvascular complications or those who experience hypoglycemic unawareness, glycemic control should be less strict. An objective of an HbA1c level between 7% and 8% may be considered adequate and may even be greater than 8% if their life expectancy is short.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Hypoglycemia is defined as a condition in which a low plasma glucose level exposes the individual to potential damage.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The value established for the definition of hypoglycemia is 70<span class="elsevierStyleHsp" style=""></span>mg/dl, because this is the threshold for activation of the counterregulatory response for individuals without diabetes and the upper limit at which the counterregulatory response to hypoglycemia changes.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Although the definition of hypoglycemia is not without debate, this is the most widely accepted definition. It should also be taken into account that the threshold of hypoglycemia perception can vary because, in cases of recurrent hypoglycemia, the symptoms of hypoglycemia occur with lower plasma glucose values, while patients with poor long-term glycemic control can experience symptoms of hypoglycemia with values greater than 70<span class="elsevierStyleHsp" style=""></span>mg/dL.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The classification of hypoglycemia is shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Statement of the problem</span><p id="par0015" class="elsevierStylePara elsevierViewall">The incidence of hypoglycemia in type 2 diabetes (DM2) varies depending on various factors and increases as the time of disease evolution increases and with the degree of insulin deficiency, as well as in cases of treatment with secretagogues and/or insulin.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Various studies have reported an incidence of hypoglycemia varying between 2.5 and 16.4 episodes per patient per year.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In a broad observational study, the incidence of serious hypoglycemia (11.8 episodes/100 patients/year) was similar for patients with type 1 diabetes (DM1) and DM2.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> A 7% frequency of severe hypoglycemia has been reported, which was similar in patients with DM2 treated with sulfonylureas or insulin, although the frequency of nonserious hypoglycemia was lower (39%) in patients treated with sulfonylureas than in the insulin group (51%).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Despite the differences found between the studies, which can be partly explained by the differences in the definition of hypoglycemia and in the method of assessing it, we can conclude that it is a significant problem in patients with DM2, especially in those treated with secretagogues and/or insulin. A recent study performed in Spain demonstrated a frequency of nonserious hypoglycemia of 0.35 episodes per patient per week for those with DM2 treated with basal insulin and oral drugs, 0.82 episodes in patients treated with basal-bolus insulin and 0.57 in patients with DM2 undergoing other insulin therapies, which corresponds to an annual frequency of 18, 42 and 30 episodes, respectively.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The healthcare impact and economic cost of hypoglycemia are considerable. The greatest expenditures are associated with serious hypoglycemia, although the direct healthcare costs described in Spain for a serious hypoglycemia episode vary significantly depending on the study: between €371 (if resolved in primary care) and €3500 (if resolved in the hospital setting).<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> A recent study performed in Spain revealed that 24.4% of hospitalizations involving DM2 are for hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Nonserious hypoglycemia has a lower economic impact, and its mean cost is estimated between €30 and €35.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Due to its greater frequency, however, nonserious hypoglycemia has significant repercussions from changes in medication, increased consumption of test strips, increased number of visits to nursing, increased need for health education and increased worker absenteeism.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Diagnosis and treatment</span><p id="par0030" class="elsevierStylePara elsevierViewall">For the diagnosis and treatment of hypoglycemia, self-monitoring of capillary glucose (SMCG) is necessary. If a glucometer is not available for determining the presence of hypoglycemia when faced with compatible symptoms, it is recommended that patients be treated as if they are experiencing hypoglycemia by administering 15<span class="elsevierStyleHsp" style=""></span>g of glucose or equivalent (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). After 15<span class="elsevierStyleHsp" style=""></span>min, patients should have their glucose levels measured, and the treatment should be repeated if the values are still below 70<span class="elsevierStyleHsp" style=""></span>mg/dL. When values greater than 70<span class="elsevierStyleHsp" style=""></span>mg/dL are achieved, it is recommended that carbohydrates be consumed to prevent a new hypoglycemic event.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Taking this into account, patients treated with drugs that entail an increased risk of hypoglycemia should have a glucometer and tests strips at hand and be trained in hypoglycemia treatment. The current recommendations suggest assessing the risk of hypoglycemia during each visit for patients treated with insulin, sulfonylureas or repaglinide through simple questionnaires that the patient can fill out before entering the doctor's office.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The recommendations on the frequency of SMCGs, depending on the situation and diabetes treatment used, are listed in a consensus document of the Spanish Society of Diabetes.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The risk of hypoglycemia differs according to the mechanism of action of the antidiabetic drugs. Treatment with metformin entails a very low risk of hypoglycemia (0.3% per year) when used as monotherapy.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In a systematic review, the risk of hypoglycemia for dipeptidyl-dipeptidase (DPP)-4 inhibitors and glitazones was equally low and comparable to that of metformin.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> However, the risk of presenting mild to moderate hypoglycemia is 3 to 7 times greater for monotherapy with sulfonylureas or glinides when compared with metformin, glitazones and DPP4 inhibitors.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> It is worth noting that this review found no differences in terms of hypoglycemia risk for sulfonylureas and glinides.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Treatment complexity influences the frequency of hypoglycemia. Therefore, nonserious hypoglycemia episodes are more common with combined therapies than in monotherapy.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The relative risk (RR) of hypoglycemia is 5.8 for the sulfonylurea-metformin combination compared with glitazone-metformin and 1.8 for metformin-glinide compared with metformin-glitazone, with no significant differences in the metformin-glitazone combination compared with metformin-DPP4i.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The glucagon-like-peptide (GLP)-1 receptor agonists are a therapeutic group characterized by a low risk of hypoglycemia, positive effects on weight and a potent normoglycemic effect, especially those with long-acting release (LAR liraglutide and exenatide). In the LEAD (Liraglutide Effect and Action in Diabetes) clinical trials program, the overall incidence of liraglutide-associated hypoglycemia varied between 0.03 and 1.9 episodes per patient per year. There were no differences in hypoglycemic episodes for the 1.2-mg dose compared with placebo,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> while the risk of hypoglycemia in the 1.8-mg liraglutide group was low, although slightly greater than that of placebo in the studies in combination with sulfonylurea (SU): 0.47 vs. 0.17 episodes/patient/year in the LEAD-1-SU study,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> 0.6 vs. 0.2 episodes/patient/year in LEAD-4,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> 0.06 and 1.2 (greater and lesser hypoglycemia, respectively) vs. 0 and 1.0 episodes/patients/year in LEAD-5 .<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Exenatide is a GLP-1 agonist of animal origin that is also associated with a low risk of hypoglycemia. In the DURATION 1–5 studies (<span class="elsevierStyleItalic">Diabetes Therapy Utilization: Researching Changes in A1C</span>, <span class="elsevierStyleItalic">Weight and Other Factors Through Intervention with Exenatide Once Weekly</span>), 13% of patients treated with exenatide weekly and 16% of those treated with exenatide twice daily experienced an episode of minor hypoglycemia, although the incidence in patients not treated with sulfonylureas was 1% and less than 1%, respectively.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In terms of the hypoglycemic risk of the various GLP-1 agonists, the incidence of minor hypoglycemia in the direct comparison clinical trials was less in the liraglutide group than in the exenatide group (liraglutide: 1.93 vs. exenatide: 2.60 episodes/patient/year; RR 0.55; 95% CI 0.34–0.88; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.0131) and was similar to weekly exenatide (liraglutide: 10.8% vs. weekly exenatide: 8.9%, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.374), despite a significantly greater effect of liraglutide on glycemic control.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,19,20</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The use of insulin analogs has been shown to reduce the risk of hypoglycemia compared with human insulin. In a meta-analysis by the National Institute for Health and Clinical Excellence (NICE), the rates of hypoglycemia were significantly lower in patients treated with insulin glargine (RR 0.89, 95% CI 0.83–0.96) or insulin detemir (RR 0.68, 95% CI 0.54–0.86) compared with neutral protamine Hagedorn (NPH).<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The advantages and disadvantages of the various drug treatment options, as well as the costs, are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical guidelines</span><p id="par0070" class="elsevierStylePara elsevierViewall">The recommendations of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) for the treatment of DM2<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> envision a patient-focused therapeutic approach, considering the patient's preferences and comorbidities as well as the risk of hypoglycemia, when choosing a specific diabetes treatment. A number of the current treatment algorithms from various scientific societies recommend the early use of GLP-1 agonists. Thus, the American Association of Clinical Endocrinologists proposes the early use of GLP-1 agonists combined with metformin or as monotherapy when there is intolerance or contraindication for this, prioritizing its use over DPP-4 inhibitors (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> The recommendations of the ADA-EASD<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> suggest the use of GLP-1 agonists in patients with DM2 in the second therapeutic step due to its positive effects on weight and low risk of hypoglycemia. The various guidelines are not in complete agreement as to where the various treatment modalities should be placed in the treatment algorithm of DM2, which undoubtedly is partly influenced by economic issues. However, given that there are no studies directly comparing several treatment modalities, the clinical guidelines are of assistance in daily clinical practice, although doctor discretion and treatment individualization are priorities.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">In terms of classification, consequences and evaluation of hypoglycemic risk, the ADA has recently published updated guidelines.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The frequency of SMCG according to the diabetes treatment and hypoglycemic risk was established by the Spanish Society of Diabetes.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Areas of uncertainty</span><p id="par0080" class="elsevierStylePara elsevierViewall">The relationship between hypoglycemia, mortality and cardiovascular events should be adequately defined, and the mechanisms responsible for this association should be clarified. Moreover, it has not been completely established whether hypoglycemic episodes are associated with cognitive dysfunction. A recent meta-analysis revealed increased mortality and increased risk of stroke in patients treated with sulfonylureas compared with those treated with other diabetic therapies.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> The authors concluded that although a cautious interpretation of the results should be conducted, the cardiovascular safety of sulfonylureas cannot be completely established until it is evaluated in prospective studies.</p><p id="par0085" class="elsevierStylePara elsevierViewall">The possible association between drugs that act on the incretin system (DPP4 inhibitors and GLP-1 agonists) and the increased risk of pancreatitis has recently been the subject of controversy. According to a number of authors,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> there are animal model data that reveal proliferative effects on the exocrine pancreas, which could explain the increased number of cases of acute pancreatitis reported in patients in treatment with GLP-1 agonists and DPP4 inhibitors. However, other authors<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> state that the benefits of these treatments clearly outweigh the potential risks, based on the lack of a causal relationship between treatment with incretin drugs and pancreatitis in humans, on the observation of an asymptomatic increase in lipase and amylase levels in patients with asymptomatic DM2 associated with pancreatitis and on a possible bias in the reporting of pancreatitis cases. This is also based on the fact that the study showing a greater number of cases in patients treated with these drugs used data from the FDA's adverse event surveillance system during a period of special alert of the scientific community, which could have prompted an increased reporting of cases that were not entirely confirmed.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> A report published by the European Medicines Agency<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> established that there are no conclusive data confirming a greater risk of pancreatic adverse effects associated with GLP-1 agonists. In addition, there was a joint report by the ADA, EASD and International Diabetes Federation<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> that established that current evidence is not sufficient to change the previously established treatment algorithms.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Recommendations and conclusion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Our case is of a young patient with a short evolution of the diabetes in which, according to current recommendations, the objective of glycemic control should be an HbA1c level of 6.5%. Although the laboratory tests revealed values close to this objective, the patient presented hypoglycemia that not only impacted the patient's quality of life<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> but was also a criterion of poor control. Therefore, the treatment should be changed in order to avoid these hypoglycemic events and improve glycemic control. This case is also about a patient with obesity in whom selecting drugs with positive effects on weight would be desirable.</p><p id="par0095" class="elsevierStylePara elsevierViewall">The possibilities of changing the treatment for this patient would be several. Firstly, proving information on the necessary changes in lifestyle (diet and exercise) would be needed, due to their importance throughout the progression of diabetes. In terms of changing the drug treatment, one option would be to discontinue use of the sulfonylurea and substitute it with another oral drug combined with metformin as a DPP4 inhibitor or pioglitazone. This last treatment modality causes increased weight, which would not be desirable in cases of obesity and is also associated with an increased risk of fracture.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The combination of a DPP4 inhibitor and metformin has a number of advantages that include the low risk of hypoglycemia and the lack of weight gain.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In terms of glycemic control, the reduction of HbA1c is similar to that observed for sulfonylureas.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Another option would be to start treatment with a GLP-1 agonist combined with metformin. In addition to the positive effects on weight, this alternative entails a more potent normoglycemic effect, which not only enables the patient to reach the goal of glycemic control but also improves the patient's weight evolution. Lastly, we can opt to add basal insulin to the treatment with metformin, although this option lacks the positive effects on weight described for GLP-1 agonists and entails an increased risk of hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conflicts of interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">Dr. P. Mezquita Raya has received honoraria as a speaker for BMS-AZ, Esteve, FAES, GSK, Lilly, MSD, Novartis, NovoNordisk and Sanofi-Aventis and as a consultant for BMS-AZ, FAES and NovoNordisk. He has also participated in research projects sponsored by Amgen, Boehringer-Ingelheim, Lilly, MSD, NovoNordisk, Pfizer, Roche,Sanofi-Aventis and Tolerx-GSK.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Dr. R. Reyes García has received honoraria as a speaker for Esteve, FAES, GSK, NovoNordisk and Sanofi-Aventis, and participates or has participated in research projects sponsored by Amgen, Boehringer-Ingelheim, NovoNordisk, Roche and Tolerx-SG.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres336657" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec318137" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres336658" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec318138" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "The clinical problem" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Statement of the problem" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Diagnosis and treatment" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical guidelines" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Areas of uncertainty" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Recommendations and conclusion" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-11-04" "fechaAceptado" => "2013-12-14" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec318137" "palabras" => array:3 [ 0 => "Hipoglycemia" 1 => "Antidiabetics" 2 => "Type 2 diabetes" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec318138" "palabras" => array:3 [ 0 => "Hipoglucemia" 1 => "Antidiabéticos" 2 => "Diabetes tipo 2" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A 58-year-old woman with type 2 diabetes diagnosed 3 years before came to our clinic. Her treatment was metformin 850<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h and glimepiride 4<span class="elsevierStyleHsp" style=""></span>mg every 24<span class="elsevierStyleHsp" style=""></span>h. After the initiation of glimepiride 9 months before her weight has increased 5<span class="elsevierStyleHsp" style=""></span>kg, and she suffers frequent hypoglycemias which have affected her while driving. Her BMI is 35.5<span class="elsevierStyleHsp" style=""></span>kg/m<span class="elsevierStyleSup">2</span>. She has a normal eye fund exam. She has hypertension treated with telmisartán and hidroclorotiazide with adequate control, and also hypercholesterolemia treated with atorvastatine 40<span class="elsevierStyleHsp" style=""></span>mg every 24<span class="elsevierStyleHsp" style=""></span>h. Her blood test shows an HbA<span class="elsevierStyleInf">1c</span> of 7.0%, normal values of microalbuminuria, total cholesterol 149<span class="elsevierStyleHsp" style=""></span>mg/dl, HDL cholesterol 52<span class="elsevierStyleHsp" style=""></span>mg/dl, LDL cholesterol 98<span class="elsevierStyleHsp" style=""></span>mg/dl and triglycerides 123<span class="elsevierStyleHsp" style=""></span>mg/dl. Her blood pressure is 129/81<span class="elsevierStyleHsp" style=""></span>mmHg, there was no orthostatic hypotension, and her peripheral neurological examination shows normal results. In summary, our case is a young woman with type 2 diabetes and obesity, without chronic complications and which has frequent hypoglycaemia. How must this woman be evaluated and treated?</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Mujer de 58 años con diabetes tipo 2 diagnosticada hace 3 años, en tratamiento con metformina 850<span class="elsevierStyleHsp" style=""></span>mg cada 12<span class="elsevierStyleHsp" style=""></span>h y glimepirida 4<span class="elsevierStyleHsp" style=""></span>mg cada 24<span class="elsevierStyleHsp" style=""></span>h. Tras iniciar glimepirida hace 9 meses ha incrementado 5<span class="elsevierStyleHsp" style=""></span>kg su peso habitual, y presenta hipoglucemias frecuentes que han afectado a su capacidad para conducir. Su índice de masa corporal es 35,5<span class="elsevierStyleHsp" style=""></span>kg/m<span class="elsevierStyleSup">2</span>. Presenta además hipertensión arterial en tratamiento con telmisartán e hidroclorotiazida con adecuado control, e hipercolesterolemia en tratamiento con atorvastatina 40<span class="elsevierStyleHsp" style=""></span>mg/día. Acude a consulta para revisión, aporta fondo de ojo, con resultado normal y resultados de la analítica que muestra una HbA<span class="elsevierStyleInf">1c</span> de 7,0%, microalbuminuria negativa, colesterol total 149<span class="elsevierStyleHsp" style=""></span>mg/dl, HDL colesterol 52<span class="elsevierStyleHsp" style=""></span>mg/dl, LDL colesterol 98<span class="elsevierStyleHsp" style=""></span>mg/dl y triglicéridos 123<span class="elsevierStyleHsp" style=""></span>mg/dl. La tensión arterial es de 129/81<span class="elsevierStyleHsp" style=""></span>mmHg, no presenta hipotensión ortostática, y la exploración neurológica periférica en miembros inferiores es normal. En resumen, se trata de una paciente joven, con una diabetes tipo 2 y obesidad, sin complicaciones crónicas, y con hipoglucemias frecuentes ¿Cómo deber ser evaluada y tratada esta paciente?</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Reyes García R, Mezquita Raya P. Como prevenir y tratar las hipoglucemias farmacológicas. Rev Clin Esp. 2014;214:202–208.</p>" ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "<span class="elsevierStyleItalic">Source</span>: Adapted from the AACE Comprehensive Diabetes Management Algorithm.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> The algorithm states the treatment recommendations of the AACE based on the initial HbA<span class="elsevierStyleInf">1c</span> values and the presence or absence of symptoms. The use of drugs marked with * is indicated hierarchically, based on its benefits and/or favorable profile of adverse effects; the rest of the drugs included in each heading should be used with caution for this reason." "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1691 "Ancho" => 1589 "Tamanyo" => 242642 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Treatment algorithm for type 2 diabetes of the American Association of Clinical Endocrinologists.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "<span class="elsevierStyleItalic">Source</span>: Adapted from Seaquist et al.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serious hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Requiring the intervention of another individual to correct it \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Documented symptomatic hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Typical symptoms of hypoglycemia accompanied by a measurement of capillary glycemia less than 70<span class="elsevierStyleHsp" style=""></span>mg/dL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Asymptomatic hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Measurement of capillary glycemia less than 70<span class="elsevierStyleHsp" style=""></span>mg/dL with no symptoms typical of hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probable symptomatic hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Typical symptoms of hypoglycemia lacking a measurement of capillary glycemia but which are assumed to be values of glycemia less than 70<span class="elsevierStyleHsp" style=""></span>mg/dL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pseudohypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Symptoms of hypoglycemia with values of capillary glycemia greater than 70<span class="elsevierStyleHsp" style=""></span>mg/dL \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab495835.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Classification of hypoglycemia.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "<span class="elsevierStyleItalic">Source</span>: Adapted from Mezquita-Raya et al.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>" "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypoglycemia treatment options: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>15<span class="elsevierStyleHsp" style=""></span>g of glucose (three 5-g tablets or equivalent)<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleHsp" style=""></span>Two or three dessert spoons of sugar dissolved in water<span class="elsevierStyleHsp" style=""></span>175<span class="elsevierStyleHsp" style=""></span>ml of juice or soft drink<span class="elsevierStyleHsp" style=""></span>15<span class="elsevierStyleHsp" style=""></span>ml (1 tablespoon) of honey<span class="elsevierStyleHsp" style=""></span>A glass of milk<span class="elsevierStyleHsp" style=""></span>A piece of fruit<span class="elsevierStyleHsp" style=""></span>3 cookies \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab495836.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">This option is preferable because it resolves the symptoms faster.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Treatment of the hypoglycemia.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "<span class="elsevierStyleItalic">Source</span>: Adapted from Inzucchi et al.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>" "tabla" => array:2 [ "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Only drugs marketed in Spain are included. The drugs marked with an * have a generic presentation; the expressed cost refers to this presentation.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Efficacy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Risk of hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Effect on weight \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Advantages \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Disadvantages \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Cost \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Metformin*</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Extensive clinical experienceProbable reduction in cardiovascular events \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gastrointestinal symptomsVitamin B<span class="elsevierStyleInf">12</span> deficiencyLactic acidosis (very uncommon) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Sulfonylureas*</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Extensive clinical experience \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Less durability of glycemic control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Repaglinide*</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Flexible dosageReduces postprandial glycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Frequent dosage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Pioglitazone</span>* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Greater durability of glycemic controlIncreased HDL, reduced TGsPossible reduction in cardiovascular events \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EdemaIncreased risk of fracturePossible increased risk of bladder cancer \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Glucosidase ∝ inhibitors</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Does not cause hypoglycemiaReduces postprandial glycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gastrointestinal symptomsFrequent dosage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">DPP-4 inhibitors</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Presentations combined with metformin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">GLP-1 antagonists</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Potential cardioprotective effects and improved beta-cell function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gastrointestinal symptoms (mild and temporary with long-acting agonists)Dosing related to consumption (short-acting agonists)Injectable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Postinjection skin reactions (weekly Exenatide) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Short-acting:</span><span class="elsevierStyleHsp" style=""></span>Exenatide<span class="elsevierStyleHsp" style=""></span>Lixisenatide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Long-acting:</span><span class="elsevierStyleHsp" style=""></span>Liraglutide<span class="elsevierStyleHsp" style=""></span>LAR Exenatide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Basal insulin</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Extensive clinical experience \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypoglycemia (less with basal analogs)Weight gain (less with insulin detemir)Injectable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ NPH+++ A. Basal \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab495837.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Characteristics of the various oral diabetic agents.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:31 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "10-year follow-up of intensive glucose control in type 2 diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R.R. Holman" 1 => "S.K. Paul" 2 => "M.A. Bethel" 3 => "D.R. Matthews" 4 => "H.A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2023 March | 7 | 4 | 11 |
| 2021 October | 1 | 0 | 1 |
| 2018 February | 104 | 0 | 104 |
| 2018 January | 68 | 0 | 68 |
| 2017 December | 87 | 0 | 87 |
| 2017 November | 54 | 0 | 54 |
| 2017 October | 14 | 0 | 14 |
| 2017 September | 11 | 0 | 11 |
| 2017 August | 6 | 0 | 6 |
| 2017 July | 7 | 0 | 7 |
| 2017 June | 13 | 0 | 13 |
| 2017 May | 14 | 0 | 14 |
| 2017 April | 3 | 0 | 3 |
| 2017 March | 10 | 0 | 10 |
| 2017 February | 7 | 0 | 7 |
| 2017 January | 9 | 0 | 9 |
| 2016 December | 12 | 0 | 12 |
| 2016 November | 3 | 0 | 3 |
| 2016 October | 7 | 0 | 7 |
| 2016 September | 13 | 0 | 13 |
| 2016 August | 10 | 0 | 10 |
| 2016 July | 6 | 0 | 6 |
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